The present invention relates to 2-aminobenzazapine derivatives which are immune stimulants with a variety of immunomodulatory activities and as such are useful in the treatment of myelosuppression including suppression associated with cancer chemotherapy as well as activation of the immune system for the treatment of cancer, and in the prevention and treatment of viral, fungal, bacterial and parasitic infectious diseases, either alone or as a vaccine adjunct in conjunction with antimicrobial therapy. This invention also relates to a method of using such compounds in the prevention and treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor.
The human blood-forming (hematopoietic) system replaces a variety of white blood cells (including neutrophils, macrophages and basophils/mast cells), red blood cells (erythrocytes), and clot-forming cells (megakaryocytes/platelets). The hematopoietic system of the average human male has been estimated to produce on the order of 4.5.times.10.sup.11 granulocytes and eythrocytes every year, which is equivalent to an annual replacement of total body weight. It is believed that small amounts of certain hematopoietic growth factors account for the differentiation of a small number of progenitor "stem cells" into the variety of blood cell lines for the tremendous proliferation of those lines, and for the ultimate differentiation of mature blood cells from those lines. Granulocyte and Granulocyte-Macrophage Colony Stimulation Factor (G-, and GM-CSF) are two of the four classes of hemopoietic growth factors known as colony stimulating factors (CSF's). GM-CSF is a growth factor which regulates the proliferation and differentiation of multipotential cells. GM-CSF has also been shown to stimulate the formation of clones of neutrophilic granulocytes and mononuclear phagocytic cells from single bone marrow cells in vitro. Colony stimulating factors also activate white blood cells to combat infections of bacteria, fungi, and parasites and accelerate the maturation of leukemic cells, thereby stopping the regeneration of leukemic cells. It is well recognized that human GM-CSF may be useful in the treatment of general hematopoietic disorders including those arising from chemotherapy or from radiation therapy. It may also be useful in bone marrow transplantation. Wound healing, burn treatment, and the treatment of bacterial inflammation may also benefit from the application of human GM-CFS.
In diseases or disease states involving immunosuppression, it is considered invaluable to restore the immune status of an individual in as rapid a fashion as possible to limit the development of opportunistic infections, bacterial, viral, fungal, etc. An agent which would stimulate the production of G or GM-CSF would augment this immunoregulation process.